Diabetes and obesity has reached epidemic levels in the patient population cared for by the Veterans Administration Medical System as well as in the general population. Obesity increases the risk for hypertension, stroke, hypercholesterolemia, heart disease, and type II diabetes. A prelude to cardiovascular disease in obesity is development of vascular dysfunction. However, the pathology linking obesity to vascular complications is not well known. In order to prevent complications associated with cardiovascular dysfunction in diabetes and obesity, it is important to improve our understanding of underlying mechanisms. Calcitonin gene-related peptide (CGRP) is a very potent physiological microvascular dilator. CGRP is released from nerve endings directly onto vascular smooth muscle to induce vasodilation. We have found that CGRP mediated dilation is attenuated in coronary arteries from high fat fed rats and in renal arteries from diabetic rats. The mechanisms involved in altered CGRP responses are not known. We believe that improving our understanding of the role of this peptide on vascular function both normal and disease models could lead to innovative therapies for vascular disease in patient populations with type 2 diabetes and obesity. The hypothesis to be tested is that abnormal vascular responses to CGRP associated with type 2 diabetes and obesity are due to decreased CGRP content in sensory nerves innervating the vasculature and alterations in degradation of CGRP, expression of CGRP receptor components and/or intracellular signaling mechanisms activated by CGRP. Our specific objectives include: 1. Determine the effect of diet induced obesity with and without type 2 diabetes on CGRP levels in the vasculature and CGRP vascular reactivity. 2. Determine mechanisms involved in vascular dysfunction associated with type 2 diabetes and obesity, including a) degradation of CGRP due to changes in expression and/or activity of NEP b) altered expression of CGRP receptor components c) alterations in activation of downstream signaling pathways following CGRP receptor activation, such as adenylate cyclase, PKA, or K+ channels. The proposed studies will use obesity resistant (OR) and obesity prone (OP) rats with and without hyperglycemia. OR rats will allow evaluation of diet on vascular reactivity. We will examine vascular reactivity in coronary, mesenteric and renal arteries. Metabolic parameters and expression of CGRP receptor components and NEP will also be determined. There is a pressing need to identify mechanisms of vascular dysfunction attributed to diabetes and obesity and to develop therapies that can prevent or reverse adverse cardiovascular consequences. With the global increase in type II diabetes and onset of obesity increasing in younger populations, the burden to deliver health care to these individuals will continue to increase. PUBLIC HEALTH RELEVANCE: Diabetes and obesity have reached epidemic levels, and increases the risk for hypertension, stroke, hypercholesterolemia, and heart disease. Health costs associated with diabetes and obesity continue to increase dramatically. Understanding mechanisms involved in cardiovascular dysfunction associated with development of diabetes and obesity is important for determining an improved standard of care to prevent or treat heart disease in these patients. We propose that improving our understanding of the role of calcitonin gene related peptide (CGRP) in vascular dysfunction associated with diabetes and obesity may lead to innovative therapies in these patient populations.